Abstract Biosemiotics and code biology are two promising approaches to understanding biological phenomena as meaningful. Biosemiotics proposes that a defining characteristic of life is code-duality, while code biology asserts that the nature of life lies in its code. However, they separated due to differences in their understanding of cellular-level interpretation, as well as related epistemological and methodological concerns. The split between the two was a great loss for biosemiotics. Meanwhile, code biology faces a conceptual dilemma when explaining the source of the normativity of organic codes without biosemiotics. The critiques of biosemiotics made by code biologists are reasonable and deserve serious concern. Based on Terrence Deacon’s thought experiment of autogenesis and his explanation of interpretation, the paper proposes the conception of operational interpretation to reconcile biosemiotics with code biology.